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Title: Alternative Binding Modes Identified for Growth and Differentiation Factor-associated Serum Protein (GASP) Family Antagonism of Myostatin

Abstract

Myostatin, a member of the TGF-β family of ligands, is a strong negative regulator of muscle growth. As such, it is a prime therapeutic target for muscle wasting disorders. Similar to other TGF-β family ligands, myostatin is neutralized by binding one of a number of structurally diverse antagonists. Included are the antagonists GASP-1 and GASP-2, which are unique in that they specifically antagonize myostatin. However, little is known from a structural standpoint describing the interactions of GASP antagonists with myostatin. In this paper, we present the First low resolution solution structure of myostatin-free and myostatin-bound states of GASP-1 and GASP-2. Our studies have revealed GASP-1, which is 100 times more potent than GASP-2, preferentially binds myostatin in an asymmetrical 1:1 complex, whereas GASP-2 binds in a symmetrical 2:1 complex. Additionally, C-terminal truncations of GASP-1 result in less potent myostatin inhibitors that form a 2:1 complex, suggesting that the C-terminal domains of GASP-1 are the primary mediators for asymmetric complex formation. Overall, this study provides a new perspective on TGF-β antagonism, where closely related antagonists can utilize different ligand-binding strategies.

Authors:
 [1];  [1];  [1];  [2];  [2];  [1]
  1. Univ. of Cincinnati, OH (United States)
  2. Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES); American Heart Association (AHA); Muscular Dystrophy Association (MDA)
OSTI Identifier:
1236259
Grant/Contract Number:  
R01AR060636; R01GM105404; 12PRE11790027; 240087
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 290; Journal Issue: 12; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Analytical Ultracentrifugation; Myostatin; Small Angle X-ray Scattering (SAXS); Structural Biology; Transforming Growth Factor Beta (TGF-B); Growth and Differentiation-associated Serum Protein; Growth and Differentiation factor-8 (GDF-8); WFIKKN

Citation Formats

Walker, Ryan G., Angerman, Elizabeth B., Kattamuri, Chandramohan, Lee, Yun-Sil, Lee, Se-Jin, and Thompson, Thomas B. Alternative Binding Modes Identified for Growth and Differentiation Factor-associated Serum Protein (GASP) Family Antagonism of Myostatin. United States: N. p., 2015. Web. doi:10.1074/jbc.m114.624130.
Walker, Ryan G., Angerman, Elizabeth B., Kattamuri, Chandramohan, Lee, Yun-Sil, Lee, Se-Jin, & Thompson, Thomas B. Alternative Binding Modes Identified for Growth and Differentiation Factor-associated Serum Protein (GASP) Family Antagonism of Myostatin. United States. https://doi.org/10.1074/jbc.m114.624130
Walker, Ryan G., Angerman, Elizabeth B., Kattamuri, Chandramohan, Lee, Yun-Sil, Lee, Se-Jin, and Thompson, Thomas B. 2015. "Alternative Binding Modes Identified for Growth and Differentiation Factor-associated Serum Protein (GASP) Family Antagonism of Myostatin". United States. https://doi.org/10.1074/jbc.m114.624130. https://www.osti.gov/servlets/purl/1236259.
@article{osti_1236259,
title = {Alternative Binding Modes Identified for Growth and Differentiation Factor-associated Serum Protein (GASP) Family Antagonism of Myostatin},
author = {Walker, Ryan G. and Angerman, Elizabeth B. and Kattamuri, Chandramohan and Lee, Yun-Sil and Lee, Se-Jin and Thompson, Thomas B.},
abstractNote = {Myostatin, a member of the TGF-β family of ligands, is a strong negative regulator of muscle growth. As such, it is a prime therapeutic target for muscle wasting disorders. Similar to other TGF-β family ligands, myostatin is neutralized by binding one of a number of structurally diverse antagonists. Included are the antagonists GASP-1 and GASP-2, which are unique in that they specifically antagonize myostatin. However, little is known from a structural standpoint describing the interactions of GASP antagonists with myostatin. In this paper, we present the First low resolution solution structure of myostatin-free and myostatin-bound states of GASP-1 and GASP-2. Our studies have revealed GASP-1, which is 100 times more potent than GASP-2, preferentially binds myostatin in an asymmetrical 1:1 complex, whereas GASP-2 binds in a symmetrical 2:1 complex. Additionally, C-terminal truncations of GASP-1 result in less potent myostatin inhibitors that form a 2:1 complex, suggesting that the C-terminal domains of GASP-1 are the primary mediators for asymmetric complex formation. Overall, this study provides a new perspective on TGF-β antagonism, where closely related antagonists can utilize different ligand-binding strategies.},
doi = {10.1074/jbc.m114.624130},
url = {https://www.osti.gov/biblio/1236259}, journal = {Journal of Biological Chemistry},
issn = {0021-9258},
number = 12,
volume = 290,
place = {United States},
year = {Thu Feb 05 00:00:00 EST 2015},
month = {Thu Feb 05 00:00:00 EST 2015}
}

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Structure of the human myostatin precursor and determinants of growth factor latency.
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Structural basis for potency differences between GDF8 and GDF11.
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